N-(phenylalkyl)-acylamide derivatives

ABSTRACT

Compounds of the formula   WHEREIN R1 and R2 may be the same or different and selected from the class consisting of alkyl groups of one to three carbon atoms, including isopropyl, R3, R4, R5, R6 and R7 may be the same or different and each selected from the class consisting of a hydrogen atom, straight and branched alkyl groups of one to three carbon atoms, straight and branched alkoxy groups of one to three carbon atoms and halogen atoms, at least two of R3, R4, R5, R6 and R7 being hydrogen and at least one of R3 and R7 being hydrogen when m is O; R8 and R9 may be the same or different and each selected from the class consisting of a hydrogen atom and straight and branched alkyl groups of one to three carbon atoms, or when R8 is hydrogen R9 may together with Am form a heterocyclic ring containing a nitrogen atom; Am is an amino group selected from the class consisting of pyrrolidino, piperidino, morpholino and monoalkylamino and dialkylamino groups in which the alkyl radicals are straight or branched and contain one to four carbon atoms; m and n is 0 or 1, at least one of m and n being 0; and therapeutically acceptable salts thereof, processes for their preparation, pharmaceutical preparations containing such compounds and their use as local anesthetics.

United States Patent 1191 Lindberg 1 N-(PHENYLALKYL)-ACYLAMIDEDERIVATIVES [75] Inventor: Ulf Henrik Anders Lindberg,

Sodertalje, Sweden [73] Assignee: Aktiebolaget Astra, Sodertalje,

Sweden Notice: The portion of the term of this patent subsequent to Oct.19, 1989, has been disclaimed.

[22] Filed: Mar. 20, 1972 21 App]. No.: 236,527

Related US. Application Data [62] Division of Ser. No. 838,313, July 1,1969, Pat. No.

OTHER PUBLICATIONS Dalal et al., J. Ind. Chem. Soc., Vol. 40, pgs.885-888 (1963). Chiavarelli et al., Gazz Ital. Chem, Vol. 81, pgs. 89-97(1951). Kudryashova et a1., Zhur. Obshch, Khim, Vol. 32, pgs. 1182-1187(1962).

Primary Examiner-Harry I. Moatz Attorney, Agent, or F irmBrumbaugh,Graves, Donohue & Raymond 11] 3,835,153 1*Sept. 10, 1974 [57] ABSTRACTCompounds of the formula Compounds of the formula I Z 0 R1 1 wherein Rand R may be the same or different and selected from the classconsisting of alkyl groups of one to three carbon atoms, includingisopropyl, R, R, R R and R may be the same or different and eachselected from the class consisting of a hydrogen atom, straight andbranched alkyl groups of one to three carbon atoms, straight andbranched alkoxy groups of one to three carbon atoms and halogen atoms,at least two of R R R R and R being hydrogen and at least one of R and Rbeing hydrogen when m is O; R and R may be the same or different andeach selected from the class consisting of a hydrogen atom and straightand branched alkyl groups of one to three carbon atoms, or when R ishydrogen R may together with Am form a heterocyclic ring containing anitrogen atom; Am is an amino group selected from the class consistingof pyrrolidino, piperidino, morpholino and monoalkylamino anddialkylamino groups in which the alkyl radicals are straight or branchedand contain one to four carbon atoms; m and n is 0 or 1, at least one ofm and n being 0; and therapeutically acceptable salts thereof, processesfor their preparation, pharmaceutical preparations containing suchcompounds and their use as local anesthetics.

2 Claims, No Drawings 1 N-(PHENYLALKYL)-ACYLAMIDE DERIVATIVES This is adivision of application Ser. No. 838,313 filed July 1, 1969, now U.S.Pat. No. 3,692,784.

The present invention relates to new N- (phenylalkyl)-acylamides andtheir salts, processes for their preparation, the therapeutic use ofsuch substances and pharmaceutical preparations containing at least oneof these new compounds.

More particularly the present invention relates to new compounds of theformula wherein R and R may be the same or different and selected fromthe class consisting of alkyl groups of one to three carbon atoms,including isopropyl, R R, R R and R may be the same or different andeach selected from the class consisting of a hydrogen atom, straight andbranched alkyl groups of one to three carbon atoms, straight andbranched alkoxy groups of one to three carbon atoms and halogen atoms; Rand R may be the same or different and each selected from the classconsisting of a hydrogen atom and straight and branched alkyl groups ofone to three carbon atoms, or when R is hydrogen R may together with Amform a heterocyclic ring containing a nitrogen atom; Am is an aminogroup selected from the class consisting of pyrrolidino, piperidino,morpholino and monoalkylamino and dialkylamino groups in which the alkylradicals are straight or branched and contain 1 to 4 carbon atoms; m andn is or 1, at least one of m and n being 0; and therapeuticallyacceptable salts thereof, processes for their preparation,pharmaceutical preparations containing such compounds and their use aslocal anesthet- ICS.

The expression therapeutically acceptable salt is recognized in the artto designate an acid addition salt which is physiologically innocuouswhen administered in a dosage and at an interval (i.e., frequency ofadministration) that is effective for the indicated therapeutic use ofthe parent compound. Typical therapeutically acceptable addition saltsof the compounds of formula 1 include but are not limited to the saltsof mineral acids, such as hydrochloric, hydrobromic, phosphoric orsulphuric acid, organic acids, such as lactic, levulinic, citric,fumaric, maleic, succinic, tartaric and benzoic acid and sulphonicacids, such as methanesulphonic and sulphamic acid.

In the art of local anesthesia the introduction of the first clinicallyuseful animoacylamide, lidocaine CHa CH H: i

initiated efforts to synthesize aminoacylamides with even morefavourable pharmacological properties. The

investigations have been largely concerned with variations in thearomatic moiety of lidocaine whereas aralkylamines have been the subjectof only a few investigations. The local anesthetic effect of2-diethyl-amino-N- (a-methylbenzly)-acetamide OzHr with an active ester,e.g. 2,4 -di-nitrophenyl ester, pnitro-phenyl ester orN-hydroxysuccinimide ester of the acid having the formula III wherein Arepresents the moiety and in which formulas R R R R R R R R R m and nare defined as above and Am is equal to Am or a group convertible intoAm by methods known per se, or with a functional equivalent of theactive esters of formula III as an acylating agent for a primary aminogroup, whereafter, when Am is not equal to Am, it is transformed into Amby methods known per se to the formation of a compound of formula I,

b. reacting a compound of the formula A NHMgHal with a lower alkyl esterof a carboxylic acid of formula Ill, in which formulas A and Am aredefined as above and Hal means a halogen atom, preferably bromine,whereafter when Am is not equal to Am, it is transformed into Am bymethods known per se to the formation of a compound of formula I,

c. reacting an isocyanate of the formula A-NCO Rs NEG-('J-Am e XII witha carboxylic acid of formula III preferably in the 5 t the'fSFia tidhdfa edmpfiu n dbfthe formula presence of a condensing agent, in whichformulas A and Am are defined as above, whereafter, when Am is not equalto Am, it is transformed into Am by methods known per se to theformation of a compound of formula I,

d. reacting a compound of the formula in which formulas A, R R and Amare as defined above, Z is a monovalent hydrocarbon radical, preferablyalkyl of at most four carbon atoms and Hal is a halogen atom, preferablychlorine,

e. reacting a compound of the formula with an amine of formula HAm inalkaline solution to the formation of a compound of formula IX, in whichformulas A, R, R and Am are as defined above and Z represents hydrogenor an alkyl group of at most four carbon atoms,

f. reacting a compound of the formula RI (CH1) w--OH in strongly acidicmedia, e.g. concentrated sulphuric acid, benzenesulphonic acid, etc,with a cyanide of the formula XIII wherein R to R, m and Am are asdefined above, whereafter, when Am is not equal to Am, it is transformedinto Am by methods known per se to the formation of a compound of theformula I,

g. reacting a compound of the formula R1 (C 2) Ill in strongly acidicmedia, e.g. concentrated sulphuric acid, benzenesulphonic acid, etc,with a cyanide of formula XII to the formation of a compound of formulaXIII, in which formulas R, R to R, m and Am are as defined above and Ris an alkylidene radical of one to three carbon atoms,

h. reacting a compound of the formula A-N H with a of the formula to theformation of a compound of the formula RB A-NH-O O-( J--Am XVII whereinA, R R and Am are defined as above,

i. reacting a salt of the formula with a dehydrating agent, wherein A,R, R and Am are defined as above, whereafter, when Am is not equal toAm, it is transformed into Am by methods known per se to the formationof a compound of formula l,

j. nitrosing a compound of the formula A NH co CH2 COOZ XIX ' which isthen ringclosed and decarboxylated by treatment with mineral acids, thecompound thus formed is precipitated by alkali and alkylated to theformation of a compound of the formula wherein A is defined as above, pis 3 0r 4 and R is an alkyl group of at most six carbon atoms, or

k. reacting a compound of the formula ANI-I with a compound of theformula H1N(CH:) won-c 0 c1 1 I XXII ringclosing the compound thusformed by treatment with alkali solution to the formation of a compoundof the formula A-NHC OCHNH CH2) XXIII which is then alkylated to theformation of a compound of formula XXI, in which formulas A, p and R aredefined as above.

Functional equivalents to the active esters of the acid of formula Illinclude the corresponding carboxylic chlorides, bromides, acidanhydrides, including mixed anhydrides and particularly the mixedanhydrides prepared from stronger acids such as the lower aliphaticmonoesters of carbonic acid, of alkyl and aryl sulphonic acids and ofmore hindered acids such as diphenylacetic acid. In addition, an acidazide or active thioester (e.g. with thiophenol, thioacetic acid), maybe used or the free acid itself may be coupled with the amine of formulaII by the use of a carbodiimide reagent. Another equivalent of the2,4-dinitrophenyl and p-nitrophenyl esters is a corresponding azolide,i.e., an amide of the corresponding acid whose amide nitrogen is amember of a quasi-aromatic five-membered .ring containing at least twonitrogen atoms, i.e., imidazole, pyrazole the triazoles, benzimidazole,benzotriazole and their substituted derivatives. Still anotherequivalent is a derivative obtained by reaction between a carboxylicacid of formula III and N-ethyI-S-phenylisoxazolium-3 -sulphonate.

The group Am when not equal to Am may be a halogen atom, preferablychlorine, which is transformed into Am by reaction with an amine offormula I-IAm.

Compounds of formula I, wherein Am is a dialkyl amino group may beobtained by reacting a compound obtained according to reaction a), b),c), or 1') wherein Am is amino or monoalkylamino with an alkylatingagent, e.g., a dialkylsulphate. Such compounds may also be obtained fromcompounds wherein Am is halogen atom by reaction with a compound of theformula wherein R and R are alkyl groups of one to four carbon atoms,whereafter the quaternary compound of the formula thus formed, whereinA, R R R and R are defined as above and Hal means halogen, ishydrogenated in a solvent, preferably in an alcohol, in the presence ofa catalyst to the formation of a compound of formula I, wherein u Am is--N According to another embodiment of reaction a) a compound of formulaII is reacted with an acid halogenide of formula III, wherein Am is aquaternary group ]Hal",

wherein R", R and Hal are defined as above and R is an aralkyl group,preferably C H CH or CH C H,,CH to the formation of a compound of theformula wherein A, R, R", R, R, R and Hal are defined as above,whereafter the group R is split off by means of catalytic hydrogenationto the formation of a compound of formula I, wherein Am 15 N The groupmay be a heterocyclic group which may be transfdr ried into iiiir'i?wherein p and R are defiri las abovfly catalytic hydrogenation ifnecessary, and treatment with an alkylating agent, or when it is thegroup a compound of formula II is reacted with a compound of the formulato the formation of a compound of the formula which is then reacted withan amine of formula I-lAm in which formulas A, R, R Am and Hal aredefined as above. Preferably Hal is chlorine or bromine.

ln therapy the compounds of thepresent invention are administered in theform of a solution in a pharmaceutical carrier. The concentration is notimportant and widely varying concentrations are therapeuticallyeffective. Typical solutions may contain from about 0.02 percent up toas high as about 10 percent by weight. The compounds according to theinvention may be administered in the form of other pharmaceuticalpreparations such as suspensions, jellies, ointments or bases. ln thesepreparations the compounds may be used in the form of their free basesor as addition salts or as both.

As is well known in the art, solutions of local anesthetics may be madeisotonic by the addition of i.a.- sodium chloride. Furthermore it isknown in the art of local anesthesia that the anesthetic effectivenessmay be improved by addition of a vasoconstrictor such as adrenaline,noradrenaline or octapressin.

The amount of local anesthetic which may be used varies widely, as iswell known, depending upon the location and type of anesthesia required.The anesthetic effect, according to the present invention, is induced byapplying an amount of N-(phenylalkyl)-acylamide solution, which iseffective to produce the desired anesthesia.

Repeated applications at therapeutically effective intervals may bemade, if desired, to obtain a prolonged effect.

it will be appreciated that certain of the compounds according to thepresent invention exist in the form of optically active isomers, whichmay be isolated in any principially known way for resolusion of anamine, and it is understood that such a manner will be included withinthe scope of the present invention. The racemates obtained at the abovereactions can be resolved into the enantiomeres by converting the freebase into a salt or an amide of an optically active acid andregeneration of the amine after the usual separation of thediastereomeric mixture thus obtained.

It will also be understood that the optically active compounds of thepresent invention may be used either as a purified isomeric productobtained as a natural consequence of the reaction sequences describedabove or any reaction sequence for the preparation of the compoundswhich results in a mixed isomeric product containing the biologicallyactive isomer or isomers.

For a further understanding of the present invention references may begiven to the following examples.

Example 1. 2-Diethylamino-N-(a,a-dimethylbenzyl)-acetamidehydrochloride.

a,a-Dimethylbenzylamine (13.5 g; 0.100 mole) was dissolved in tolueneml), 10 percent sodium hydroxide 100ml) was added and the stirredmixture was cooled to 5C. Chloroacetyl chloride (19.9 g; 0.176 mole) wasadded dropwise during 5 minutes, whereupon the temperature rose to about20C. The crystalline 2-chloro-N-(a,a-dimethylbenzyl)-acetamideprecipitated within 30 minutes, was filtered off, washed on the filterwith cold toluene and water, dried in vacuo and recrystallized fromtoluene after decolourizing with carbon. Yield: 19.1 g (90.1 percent);m.p. 8789C.

A solution of the aforementioned chloroacetamide (9.7 g; 0.046 mole) anddiethylamine (8.7 g; 0.119 mole) in dry benzene (50 ml) was boiled underreflux for 5 hours. The reaction mixture was diluted with absolute ether(50 ml) and filtered to remove the diethylamine hydrochloride formed.The solution was extracted with 5 N hydrochloric acid, the aqueous phasewas made alkaline with 5 N ammonia and extracted with benzene andchloroform.

The organic phase was dried over sodium sulphate and the solvents wereremoved in vacuo. The residual crude oil was distilled under vacuumaffording an almost colourless, viscous liquid boiling at C/0.l0 mm Hg.Yield: 10.0 g. (87.8 percent).

The above liquid base, 2-diethylamino-N-(a,adimethylbenzyl)acetamide,was converted to a crystalline hydrochloride in the following way:

To a cooled solution of the base (5.0 g; 0.021 mole) in dry ether wasadded dropwise a slight excess of the required amount of hydrochloricacid dissolved in dry ether. The precipitated crude salt was dried undervacuum over phosphorous pentoxide and recrystallized from ethanol-ether.Yield: 5.3 g (92.6 percent), m.p. 9395C. The total yield of2-diethylamino-N-(a,adimethylbenzyl)-acetamide hydrochloride startingfrom a,a-dimethylbenzylamine was thus 73.2 percent.

Example 2. N-( a,a-Dimethy lbenzyl )-2-n-propylaminoacetamidehydrochloride.

A solution of 2-ch1oro-N-(a,a-dimethy1benzyl)- acetamide (9.5 g; 0.045mole) (prepared as described in Example 1) and n-propylamine (7.3 g;0.123 mole) in dry benzene (50 ml) was boiled under reflux for hours.The reaction mixture was diluted with absolute ether (50 ml) andfiltered to remove the n-propylamine hydrochloride formed. On attemptedextraction of the product base from the ethereal phase with 5 Nhydrochloric acid the crystalline N-(a,a-dimethylbenzy1)-2-n-propyl-amino-acetamide hydrochloride precipitated, was filtered off,washed on the filter with dry ether and recrystallized from isopropanolYield: 7.8 g (64.5 percent); m.p. 228229C.

Example 3. N-( a,a-Dimethylbenzyl )-2-piperidino-propionamidehydrochloride.

a,a-Dimethy1benzy1amine (13.5 g; 0.100 mole) was dissolved in toluene(100 ml), percent sodium hydroxide (100 ml) was added and the stirredmixture was cooled to 5C. 2-Bromopropionyl bromide (38.0 g; 0.176 mole)was added dropwise during 5 minutes, whereupon the temperature rose toabout 25C. The crystalline 2-bromo-N-( a,a-dimethy1benzyl propionamideprecipitated within 10 minutes, was filtered off, washed on the filterwith cold toluene and water, dried in vacuo and recrystallized fromtoluene after decolourizing with carbon. Yield: 23.2 g (85.3 percent);m.p. 101-102C. I

A solution of the aforementioned bromopropionamide (8.6 g; 0.032 mole)and piperidine (7.2 g; 0.085 mole) in dry benzene (35 ml) was boiledunder reflux for 5 hours. The reaction mixture was worked up in analogywith the description in Example 1. The distilled oil, b.p. 124C/0.05 mm.Hg, crystallized in the cold. The colourless crystals ofN-(a,a-dimethylbenzyl)-2- piperidinopropionamide (7.7 g; 88.5 percent)melted at 59-6lC.

The above solid base was converted quantitatively to a hydrochlorideaccording to the method described in Example 1. The total yield ofN-(a,a-dimethylbenzyl)- 2-piperidinopropionamide hydrochloride (m.p.l78-180C) starting from a,a-dimethylbenzy1amine was thus 75.4 percent.

Example 4. 2-n-propylamino-N-( a,a,p-trimethylbenzyl)-acetamidehydrochloride.

2-Ch1oro-N-(a,a,p-trimethylbenzyl)-acetamide was prepared from a,a,p-trimethylbenzylamine in accordance with the methodfor thepara-unsubstituted homolog described in Example 1. Yield: 93.7 percent;m.p. 109l10C.

This chloroacetamide was reacted with npropylamine and the formedproduct worked up as described in Example 2 to give the hydrochloride of2-n- 10 propy1amino-N-(a,a,p-trimethylbenzyl )-acetamide. Yield afterrecrystallization from ethyl methyl ketonc: 57.5 percent; m.p. 189-191C.

When the acid mother liquor was made alkaline with 5 N ammonia andworked up as described in Example 1 a yield of 25.8 percent of distilled2-n-propylamino- N-(a,a,p-trimethylbenzyl)-acetamide (b.p. 136C/ 0.03 mmHg) was obtained.

The total yield of product (as base and hydrochloride) froma,a,p-trimethyl-benzylamine was thus 78.0 percent.

Example 5. 2-Pyrrolidino-N-(a,a,p-trimethylbenzy1)- propionamide.

2-Bromo-N-(a,a,p-trimethylbenzyl)-propionamide was prepared in analogywith the method described in Example 3. Yield 95.5 percent; m.p.123124C.

This bromopropionamide was reacted with pyrrolidine and the reactionmixture worked up as in Example 1. The distilled oil (b.p. 153C/0.20 mmHg) crystallized to 2-pyrrolidino-N-(a,a,p-trimethylbenzyl)-propionamide. Yield: 85.0 percent; m.p. 60-63C. The total yield froma,a,p-trimethylbenzylamine: 81.1 percent.

Example 6. 2-Diethylamino-N(a,a,m-trimethylbenzy1)- propionamidehydrochloride.

Example 7. 2-Diethylamino-N-( a,a-diethylbenzyl )-acetamide.

2-Chloro-N-(a,a-diethylbenzy1)-acetamide was prepared froma,a-diethylbenzylanime in analogy with the method in Example 1. Yield:89.4 percent; m.p. 106-107C.

This chloroacetamide was reacted with diethylamine and the formedproduct base (yield 74.0 percent, was worked up (b.p. 143C/0.1 mm Hg)but it was not possible to convert it to the corresponding hydrochloridein the usual way. n 1.5066.

Example 8. N-(a,a-Diethy1benzyl )-2-morpholinopropionamide.

2-Brom0-N-(a,a-diethylbenzyl)-propionamide was prepared in analogy withthe method in Example 3. Yield: 92.3 percent; m.p. 111-113C.

This bromopropionamide was reacted with morpholine and the formedproduct base (b.p. 172C/0.l mm Hg; m.p. 52-55C) was worked up in theusual way (see Example 1).

The total yield of N-(a,a-diethylbenzyl)-2-morpholino-propionamide froma,a-diethy1benzylamine was'79.6 percent.

Example 9. Z-Diethylamino-N-(mar-dimethylphenethyl)-acetamidehydrochloride.

a,a-,Dimethylphenethylamine (29.8 g; 0.200 mole) was dissolved intoluene (200 ml), 10 percent sodium hydroxide (200 ml) was added and thestirred mixture was cooled to C. Chloroacetyl chloride (39.8 g; 0.352mole) was added dropwise during 5 minutes, whereupon the temperaturerose to about 20C. As no precipitate was formed within 2 hours, thetoluene phase was separated and the alkaline layer extracted withtoluene. The combined toluene solutions were dried over sodium sulphateand the solvent was removed in vacuo affording a crystalline residue of2- chloro-N-(oamdimethylphenethyl)-acetamide. Yield afterrecrystallization from light petroleum: 86.6 percent; m.p. 6062C.

A solution of the aforementioned chloroacetamide (5.5 g; 0.024 mole) anddiethylamine (4.7 g; 0.064 mole) in dry benzene (25 ml) was boiled underreflux for 5 hours. The reaction mixture was diluted with absolute ether(25ml) and filtered to remove the diethylamine hydrochloride formed. Thesolution was extracted with 5 N hydrochloric acid, the aqueous phase wasmade alkaline with 5 N ammonia and extracted with benzene andchloroform.

The organic phase was dried over sodium sulphate Example 10. N-(a,a,-Dimethylphenethyl )-2-piperidinoacetamide.

A solution of 2-ch1oro-N-(or,a-dimethylphenethyl)- acetamide (5.5 g;0.024 mole) (prepared as described in Example 9) and piperidine (5.5 g;0.065 mole) in dry benzene (25 ml) was boiled under reflux for 5 hours.

The reaction mixture was worked up as described in Example 9. Theproduct base (b.p. 114 1l5C/0.03 mm Hg) solidified after distillationand was recrystallized from light petroleum. Yield 79.1 percent; m.p. 49C. The total yield of N-(a,a-dimethylphe nethyl)-2-piperidinoacetamidefrom mar-dimethylphenethylamine was thus 68.5 percent.

Example 11. N-(a,a-Dimethylphenethyl)-2-npropylaminopropionamidehydrochloride.

a,a,-Dimethylphenethylamine (29.8 g; 0.200 mole) was dissolved intoluene (200 ml), 10 percent sodium hydroxide (200 ml), was added andthe stirred mixture was cooled to 5C. 2-Bromopropionyl bromide (76.01 g;0.352 mole) was added dropwise during 5 minutes, whereupon thetemperature rose to about 25C. The crystalline2-bromo-N-(mar-dimethylphenethyl)-propionamide precipitatedimmediate1y,'was tiltered off, washed on the filter with cold tolueneand water, dried in vacuo and recrystallized from toluene afterdecolourizing with carbon. Yield: 91.1 percent; m.p. -106C. I

A solution of the aforementioned bromopropionamide (7.0 g; 0.025 mole)and n-propylamine (3.8 g; 0.064 mole) in dry benzene (25 ml) was boiledunder reflux for 5 hours. The reaction mixture was worked up asdescribed in Example2. The precipitated N-(a,adimethylphenethyl)-2-n-propylaminopropionamide hydrochloride was recrystallized fromisopropanol. Yield 69.4 percent; m.p. 191192C. The total yield ofproduct from a,a-dimethylphenethylamine was thus 63.2 percent.

Example 12. N-(a,a-Dimethyl-p-chlorophenethyl)-2-npropylaminoacetamidehydrochloride.

2-Chloro-N -(a,a-dimethy1-p-chlorophenethyl)- acetamide was preparedfrom a,a-dimethyl-pchlorophenethylamine in analogy with the method inExample 1. Yield: 94.6 percent; m.p. 99100C. This chloroacetamide wasreacted with n-propylamine and the formed product hydrochloride wasworked up as described in Example 2.

The total yield ofN-(a,a-dimethyl-pchlorophenethyl)-2-n-propylaminoacetamide hydrochloride(m.p. l9ll92C) from a,a-dimethyl-pchlorophenethylamine was 80.4 percent.

Example 13. N-((1,0:-Dimethyl-p-chlorophenethyl)-2-morpholineacetamide.

A solution of 2-chloro-N-( a,a-dimethyl-pchlorophenethyl) acetamide (9.6g; 0.037 mole) (prepared as described in Example 12) and morpholine (8.8g; 0.101 mole) in dry benzene (40 ml) was boiled under reflux for 5hours. The formed product base, which was worked up in the usual way(see Example 1) and solidifiedwithout distillation under vacuum, wasrecrystallized from light petroleum. The total yield ofN-(a,a-dimethyl-p-chlorophenethyl)-2- morpholinoacetamide (m.p. 8689C)from apt-dimethyl-p-chlorophenethylamine was 72.0 percent.

Example 14. Pipecolic and N'-n'-butylpipecolic acidN-(a,a-dimethylbenzyl)-amide.

a,a-Dimethylbenzylamine (22.4 g; 0.166 mole) was dissolved in toluenem1), triethylamine (230 ml) was added and the stirred mixture heated to55C. Pipecolic acid chloride hydrochloride (36.4 g; 0.199 mole) wasadded in small portions during 1 hour, whereupon the temperature waskept at 5560C. After a further period of 3 hours at the same temperaturethe reaction mixture was coiled and the theoretical amount oftriethylamine hydrochloride filtered off. The filtrate was mixed withwater (300 ml) and the resulting suspension allowed to settle. Thetoluene layer was separated and the aqueous phase extracted with tolueneand ether. The combined organic solutions were dried and evaporated invacuo.

The residual crude oil was distilled twice under vacuum (b.p.148-149C/0.05 mm Hg), dissolved in dry ether and filtered to removeundissolved impurities. The solvent was then evaporated affording acolourless oil (Yield: 7.3 g (29.7 percent)].

The aforementioned pipecolic acid N-(a,a-dimethylbenzyl)-amide (7.3 g;0.029 mole) was dissolved in nbutanol (35 ml), potassium carbonate (3.5g) and nbutylbromide (4.3 g; 0.031 mole) was added and the stirredmixture refluxed for 72 hours. The reaction mixture was filtered toremove inorganic salts and the liltrate evaporated in vacuo. The residuewas taken up in diluted hydrochloric acid, the solution was washed withether and made alkaline with ammonia. The alkaline phase was extractedwith ether, the etheral solution dried over sodium sulphate, filtered,treated with carbon and evaporated in vacuo. The crude residue wasdistilled under vacuum, the fraction boiling at l39C/0.l mm Hg (3.1 g),which did not crystallize, was dissolved in dry ether and filtered toremove undissolved impurities (0.2 g). The basic product dissolved inthe ethereal filtrate was converted to the corresponding hydrochloride,N'-n-butylpipecolic acid N-(a,a-dimethylbenzyl)-amide hydrochloride[m.p. 203206C (from acetone), yield: 2.4 g (73.9 percent)], in the usualway (see Example 1 Example 15. 2-Diethylamino-N-( a,a-dimethylbenzyl)-acetamide.

To a stirred mixture of N,N-diethylaminoacetonitril (22.5 g; 0.200 mole)and concentrated sulphuric acid (32.0 g; 0.310 mole) kept at about 60C asolution of a,a-dimethylbenzyl alcohol 13.6 g; 0.100 mole) in glacialacetic acid (150 ml) was added during 30 minutes.

Stirring was continued and temperature maintained at 60-65C for 5 hoursand then at C for 16 hours. The reaction mixture was then poured intoice-water, made alkaline with sodium carbonate and extracted with ether.The ethereal solution was washed with water and extracted with 5 Nhydrochloric acid. The aqueous phase was made alkaline with sodiumcarbonate again extracted with ether, which after washing with water wasdried over sodium sulphate. Evaporation of the ether afforded a lightyellow oil, which was distilled under vacuum to yield a first fractionof unchanged N,N-diethylaminoacetonitri1[ 12.3 g (54.6 percent)] and asecond fraction consisting of 2-diethylamino-N-(a,a-dimethylbenzyl)-acetamide (b.p. 124C/0.80 mm Hg),yield 0.7 g; 3.0 percent).

Example 16. 2-Dimethylamino-N-( a,a-dimethylbenzyl )-acetamide.

. ferred method, that is by reacting a compound of the with a compoundof the formula to the formation of a compound of the formula which isthen reacted with an amine of the formula HAm in which formulas R R R,R, R R R R, R and Am are as defined above. In the Tables are alsoindicated the. pharmacological effects of some of the compounds of thepresent invention relative to lidocaine. The effects of the knownsubstance 2-diethylamino-N- (a-methylbenzyl)-acetamide are also given.

The melting point given for the substances according to Examples 17-99below generally refer to the hydrochloride of the base. However, thephysical data given for the compounds according to Examples 19, 20, 23,24, 28, 33, 35, 39, 41, 44, 48, 52, 54, 60, 61, 62, 63, 64, 65, 72, 75,84, and 96, refer to the free base.

TABLE 1 PHARMACOLO GICAL DATA 0F COMPOUNDS OF THE FORMULA I RELATIVE TOLIDOCAINE (ON A MOLAR BASIS) Anaesthetic M.P., (3., Topical Toxicity 3index 4 Example B.P., C./ lated anaesnumber mm. Hg R R R N R R .R Amnerve 1 thesis 2 I.v. 8.0. I.v. 8.0.

1.0 1.0 1.0 1.0 1.0 1.0 0.1 0.0 0.4 0.3 0.0 0.0 H H H H 0. 1 0. 9 0. 5 HH H H N(Q2 0.4 0 6 0.4 0. 3 1.5 2. 0 H H H H H NH-n-C H-l 0. 3 0. 8 0. 40. 3 2.0 2. 7 H H H H H N/ 0. 1 0. 6 0. 2

18 -169 H H H H H H H O 0. 3 0. 5 0. e 0. 5 0.8 1. 0 19 42.5-44.5 H H HH H H H 0,2 0,7

37438 H H H H H H CH N(CH )2 0.2 0.2 0.2 -177 H H H H H H CH; N(C2H5)z0. 7 0. 9 0. 4 0. 4 2. 3 2. 3 11 H H H H H CH; 0. 2 0. 9 0. 5 0. 61.8 1. 5

1 TABLE 1- Continued PHA RMACOLO GICAL DATA OF COMPOUNDS OF THE FORMULAI RELATIVE TO LIDOCAINE (ON A.MOLAR BASIS)C011.

Annosthotlc M.P., C., Iso- Topical Toxicity 3 index Example B.P., C./lated anaesnumber mm. Hg R R R R" R R R Am nerve 1 thesin I.v. 5.0. Lv.8.0.

3 l -4.9.5 H H H H H H CH 0.6 0.5 0.5

3 H H H H H H OH; 3 0.6 0.7 0.6 0.7 1. .0

4 81-83 H H H H H H CH 0.1 0.4

151-100 CH3 H H H H H H N(C=H 1)1 0. s -255 CH H H H H H H NH-n-C H7 0.3 243 CH H H H H H CH3 N(C2H0)a 0- 4 46-48 OH; H H H H H CH N H-n-CzHy0. 2 1 93-100 H OH; H H H H H N (021102 0. 3 227-228 H CH H H H H H NH-fl-C H1 0. 2 100-103 H CH; H H H H H N/ 0.1

32- 159-161 H CH H H H H H N: 0. 7 1. 0 0. 6 0. 6 1. 7 1. 7

33 57-60 H CH H H H H H 0.4 1.0

W 6. H OH: H H H H CH3 N(C2Hs)2 0.3 0,7 0.8 0.6 0.9 1.2 34 187-189 H C 3H H H H C Ha N H-fl-C1H1, 0. 8 35 34-36 H CH H H H H CH N/ i 0. 3 0. 50. 7 0. 5 0. 7 1. 0

a0 123-175 H CH; 11 H H H CH C 0.0 1.0 0.11

37 '96-106 H CH H H H H CH3 r/ 0. 7 0. 6 0. 3 0. 4 2. 0 1. 5

H OH: H H H H N(C1Hs)2 0.7 1.0 0.7 0.4 1.4 2.5 H CH; H H H HNH-fl-CaH1 1. 0 0. 0 0. 8 0. 6 0. 8 1. 0 39 65-605 H H OH; H H H H N/ I2 0.8 5 0.3 1.6 2.7

L Y 40 170-172 H H OH; H H H H N: 0. Q 0. 9 0. 7 0. 4 1. 3 2. 3

41 91-93 H H CH H H H H 0.4 0.3 1.3 1.3 0.3

. 42 178-179. 5 H H OH: H H H CH3 N(C2H:1)z 1. 1 1. 3 0. 7 0. 4 1. 9 3.3 43 207. 5-208. 5 H H CH H H H CH NH-fl-CgH 1. 3 1. 1 0. 8 0. 9 1. 4 1.2 s H H CH H H H 011, N/ J 0.0 0.0 0.5 1.5 1.8

L 44 35.5-37 H H CH H H H CH N: 0.6 1.4 1.0 0.7 1.4 2.0

45- -129 H H CH H H H CH3 0. 1 0. 5 0. 2 0. 3 2. 5 1. 7

139-140 OH; H H OH; H H H N(C2Hfl)2 0. G 0. 7 0. 6 235-236 OH; H H CH3 HH H 45-47 CH3 H H CH3 H H CH: 211-213 CH H H CH3 H H CH 225-226 CH0 HOH; H OH; H H 209-210 CH3 H t CH; H CH H CH;

14 H H H H H 52 134/0. 02 H H OCH; H H H H N(C1H1)1 0.1 0. 5 0. a 53183-184 H H OCH; H H H H NH-n-CgHv 0. 1 0. 5 '0. 5 54 40-51 H H 0011. HH H H C 0. 5

55 -187 H H OCH3 H H H CH; N(C2H5): 56 182-183 H H H H H CH;

OCH;

TABLE 1-Continued PHARMACOLOGICAL DATA F COMPOUNDS OF THE FORMULA 1RELATIVE TO LIDOCAINE (ON A MOLAR BASED-Con.

. Anaesthetic M.P., 0., Iso- Topical Toxicity 3 index 4 Example B.P.,C./ lated anaesnumber mm. Hg R R R R R B R Am nerve thesis 9 l.v. S.c.I.v. 5.0.

57 148-150 H H OCH; H H H CH; N 0.3 1.0 0.6

58 122-124 H H C1 H H H H N(CH5)1 0.3 1.0 0.7 0. 5 1.4 2.0 59 189-190 HH C1 H H H H NH-n-CzH1 0.6 0.3 0.6 60 72-74 H H Ci H H H H N/ 0.5 0. 70.5 0.5 1.4 1.4

61 76-78 H H Cl H H H H N/ 0.7 1.8 0.5 1.4 3.6 1.4

62 95-97 H H Ci H H H H N 0.4 1.0 2.8

63 54-56 H H Cl H H H CH N(C2H 0.7 1.0 0.8 0.5 1.3 2.0 64 52-53 H H Ci HH H CH -IL-C3H7 1.0 1.5 0.8 1.3 1. 9 1.2 65 1. 84. 5-86 H H C1 H H H CHN/ 0.3 1.0 0.6 0.5 1.7 2.0

g 66 110-116 H H Cl H H H CH N/ 0.9 1.0 0. 7 0.5 1.4 2.0 67 1- 140-142 HH 01 H H H CH, N/ 0.2 0.2 0.3

68 55-60 H H H H H CH3 CH3 NH-Il-CaH- TABLE 2 Pharmacological data ofcompounds of the formula I relative to Lidocaine (on a. molar basis) IR=R C H m=n=0; R =R--R==R =R =H] "7 Anaesthetic Topical Toxicity 3 index4 Isolated anaes- N Example number M.P., "C R Am nerve 1 thesis. 2 I.v.S.c. I.v. 8.0. 7 H N(CzH5)2 1.1 0.9 0.5 0.6 1 8 1.5 69 263-264 HNH-7b-C3H7 0.5 0.7 70 254-156 H N/ 0.8 1.0 0.6 0. 8 1 7 1.3

72 60-70 H N/ \O 0.3 O. 5 0. 7 1. 4 0. 7 0. 4

73 203-205 CH3 N(CH5)2 0.3 0. 9 1. 0 1. 5 0. 9 0. 6 74 70-90 CH3NH-n-C3H1 0. 7 2. 6 1.2 1. 5 2. 2 1.7 75 44-47 CH3 N/ 0. 7 1. 3 1. 5 1.3 9 1. 0

s CH3 0.3 0.2 0.2 1.2 1.0 -0.2

Lidocaine 1. 0 1. 0 1. 0 1. 0 1. 0 1. 0

TABLE 3 (Pharmacological data of compounds of formula 1 relative toLidocaine (on a. molar basis) 1= z= a= 4= e= 1= a= Anaesthetic M.P., C.Topical Toxicity 3 index 4 Example B.P., C./ Isolated anaesnumber mm. Hgm n R R Am nerve 1 thesia 1 LV. S.c. I.v. S.c. Lidocaine 1. 0 1. 0 1.0 1. 0 1. 0 1. 0 I O H H N(C1H 0.7 0.9 0.6 0.6 1.5 1.5 154-155 I O H HNH-n-C3H1 0.9 1.6 1.0 1.2 1.6 1.3 78 181-182 I O H H N/ 0. 8 1. 0 0. 60. 6 1. 7 2. 0

TABLE 3 Con tinue d (Pharmacological data of compounds of formulalrelative to Lidcain0 (on a molar basis) [Rl=R2=CH a= 1= n= 1= s=mAnaesthetic M.P., C. Topical Toxicity 3 index 4 Example B.P., C./Isolated anaesnumber mm. Hg 70 n R5 R Am nerve thesla 2 1.1 8.0. 1.7.8.0.

I 0 H H 2.0 2.0 0.0 0.5 2.0 5.2

70 132-133 I 0 H H 0.3 04 0.4 0.0 1.0 0.4

s0 102-103 1 0 H CH1 M01115 0.0 1.0 0.8 0.7 1.3 1.4 11 I 0 H CH;NH-n-OnH 0.3 1.1 1.2 1.1 0.0 1.0

31 132-133 I 0 H CH 1.5 1.1 1.2 0.0 0.9 1.8

32 145-140 I 0 H CH; 0.8 1.3 1.4 0.5 0.3 2.0

33 113-115 I o H CH 0.7 0.3 0.6

s4 170/00 I 0 01 H M01115 0.2 1.5 0.4 0.0 3.8 2.5 12 1 0 01 H NH-H-C H-0.7 1.0 0.8 1.0 2.0 1.0

85 185-186 I 0 o1 H v I 00 1.0 0.7 0.0 2.7 3.2

87 211-212 I 0 01 CH; 02115 0.3 3.0 00 1.1 3.3 7 88 221-222 I o 01 OH;men-03H, 0.4 2.3 00 1.5 2.9 1.

89 44-43 I 0 c1 CH3 l 0.2 1.9 1.0 1.1 1.9 1.7

a N W -00 0 I H H N C2H3l2 0.0 107-100 0 1 H H NH-n-C2H 1.3 133-100 0 1H CH5 02115): 132-134 0 1 H CH3 NH-n-C3H1 1.5 151-152 0 1 CH3 H 01115)?224-220 0 1 CH3 H NH-n-C3Hi 1435-1450 0 1 0H CH3 M04115 M 190-192 0 I033 CH: NH-n-C H 1.5

The tests were carried out according to the following TABLE 4 list.Corresponding figures are given in the Tables. l. Frog. Relativeactivity at 5 min incubation (5 m M Example structural 011111118solutions).

2. Rabbit cornea. 0.25 ml applied. Exposure time 0.5 26 E min. Relativeduration. (|JNHCOCHNHC3H1 3. Toxicity relative to lidocaine on a molarbasis. CH3 1.13 for lidocaine: 0.94 10* moles/kg i.v. 0.93 10 CH;moles/kg so. 37

4. Ratio between relative topical anesthetic activity @o-zmcoomw /b andrelative toxicity. CH3 CH3 Compounds exhibiting particularly shortonset. low CH1 4 degree of tissue toxicity, high frequency ofanaesthesia, 88 CH; and long and reproducible duration of anaesthesia,are HaC NHCOCH2N(C2H5)2 listed in Table 4 below: I

I 7 CH3 TABLE 4 s0 (3H3 CIGC-NHCOCHzN Example Structural formula 1 1 0H13 on. can

(|3NHCOCII2N(C2H1)2 CIQ(IJ-NHCO(FHN on. I V 011, 0113 c211,

TABLE 4 :Cm hued Example Structural formula on. Cl-0NHCOCHN 211; 3H,

can @t z-Nuo o CHzN(CzH5)2 Of the compounds listed in Table 4, thoseaccording to Example 65, 13 and 12 exhibit an especially long durationof anaesthesia.

The following Examples will illustrate the preparation of pharmaceuticalpreparations containing substances of the invention.

Example 100. lnjectible solution containingN-(a,a-dimethylphenethyl)-2-(diethylamino)- acetamidc.

To l00 ml of hot, sterilized water 0.1 g of methyl phydroxybenzoate wereadded while stirring and heating. When all benzoate were dissolved 2 gof N-(a,adimethylphenethyl)-2-diethylamino)-aeetamide hydrochloride and0.6 g of sodium chloride were added while stirring. pH was adjusted to 7by adding sodium hydroxide and sterilized water was added to I00 ml.

Example 101. lnjectible solution containingN-(a,a-Dimethyl-p-chlorophenethyl)-2-npropylaminoacetamide.

To 100 ml of hot, sterilized water 0.l g of methyl phydroxybenzoate, 2 gof N-(oaa-dimethyl-pchlorophenethyl)-2-n-propylaminoacetamidehydrochloride and 0.6 g of sodium chloride were added in the same way asdescribed in Example 100, but the solution was protected from air-oxygenby working in nitrogen atmosphere. 0.05 g of sodium pyrosulphite werethen dissolved, whereafter 1 mg of adrenaline was added. pH was adjustedto 4 by adding sodium hydroxide and sterilized water was added to 100ml.

Example 102. Pharmaceutical jelly containingN-(a,a-dimethyl-p-chlorophenethyl )-2- morpholinoacetamide.

To ml of distilled water 0.5 g ofN-(a,a-dimethylp-chlorophenethyl)-2-morpholinoacetamide were added. Tothis solution 4 g of methylcellulose were added while stirring and whenall methylcellulose was dissolved a solution of 50 mg of chlorhexidinediglyconate in 10 ml of water was added and the volume was adjusted toml by addition of distilled water.

Example 103. Pharmaceutical ointment containing 2-morpholino-N-(a,a,m-trimethylbenzyl propionamid.

Equal amounts (27 g of each) of polyethyleneglycol 300 andpolyethyleneglycol 1540 were melted together with 19 g ofpolyethyleneglycol 3000 at 60C. Then 25 g of propyleneglycol and finally2 g of 2-morpholino-N- (a,a,m-trimethylbenzyl)-propionamide were addedand the ointment was homogenized.

What is claimed is:

1. The compound of the formula and the therapeutically acceptable saltsthereof.

2. The compound of the formula and the therapeutically acceptable saltsthereof.

'zgz gg UNITED STATES PATENi OFFICE CERTIFICATE OF CORRECTION Patent No.3 35,] 53 Dated September 10, 1974- lnventofls) Ulf Henrik AndersLindberg It is certified that errorappeats in the above-identifiedpatent and that said Letters- Patent are hereby corrected as shownbelow:

1 Col. 2, line 5, "methylb enzly" should read methylbenzyl--;

Col 11, line 53, "49 c" should read :49? a 50C v Signed thi s 3rd d a jof i De c ember 1974.

(SEAL) V Att'est: V v

McCOY M. GIBSON JR c. MARSHALL DANN Attesting Officer I v Commissionerof Patents

2. THe compound of the formula